REGULATION OF INTERLEUKIN-6 (IL-6)

白细胞介素-6（IL-6）是一种具有多种功能的炎性细胞因子 包括体液和细胞免疫应答的调节， 诱导血小板生成。 目前正在开发中， 化疗后诱导血小板的治疗剂。 因为IL-6作为一些造血肿瘤的生长因子（例如， 多发性骨髓瘤），设计用于调节合成或 IL-6的活性也在研究中。 目前的目标是 我们的工作是阐明IL-6水平调节的机制， vivo. 我们正在为此目的开发一种小鼠临床前模型。 实验系统包括注入矿物油降植烷 注入BALB/c小鼠的腹腔。 这种治疗会导致 慢性腹膜炎伴随着显著升高的水平 通过生物测定和ELISA测定腹腔内IL-6。 先前 研究表明，IL-6的升高可以被抑制， 与环加氧酶抑制剂吲哚美辛共同给药。 最近，我们发现IL-6的增加与 内源性前列腺素E2水平升高。 结果提示 炎症巨噬细胞分泌的类胡萝卜素可能是 负责刺激IL-6的产生在相同的细胞，通过 正反馈回路 类似的机制可能有助于 在人类疾病中，白藜芦醇和IL-6都是 慢性升高（例如，类风湿性关节炎;克罗恩病）。 初步结果表明，诱导环氧合酶基因表达， 负责刺激巨噬细胞IL-6的合成。 此外，本发明还提供了一种方法， 为了证实这一发现，我们将研究其他因素的作用。 炎症因子（例如，一氧化氮），可能影响IL-6水平 通过调节蛋白质清除率。

Interleukin-6 (IL-6) is an inflammatory cytokine with diverse functions including regulation of the humoral and cellular immune response and induction of thrombopoiesis. It is presently under development as a therapeutic agent for induction of platelets following chemotherapy. Because IL-6 acts as a growth factor for some hematopoietic tumors (e.g., multiple myeloma), protocols designed to regulate the synthesis or activity of IL-6 are also being investigated. The goal of the present work is to elucidate the mechanisms whereby IL-6 levels are regulated in vivo. We are developing a murine pre-clinical model for this purpose. The experimental system involves injection of the mineral oil pristane into the peritoneal cavities of BALB/c mice. This treatment induces a chronic peritonitis that is accompanied by dramatically elevated levels of intraperitoneal IL-6 as determined by bioassay and ELISA. Previous studies showed that the elevation in IL-6 can be inhibited by co-administration of the cyclooxygenase inhibitor indomethacin. Recently, we have found that the increase in IL-6 is associated with an elevation in endogenous prostaglandin E2 levels. The results suggest that prostaglandins secreted by inflammatory macrophages might be responsible for stimulating IL-6 production in the same cells through a positive feedback loop. A similar mechanism may contribute to the pathogenesis of human diseases in which both prostaglandins and IL-6 are chronically elevated (e.g., rheumatoid arthritis; Crohn's disease). Preliminary results show that induction of cyclooxygenase gene expression is responsible for stimulating macrophage IL-6 synthesis. In addition, to confirming this finding, we will investigate the role of other inflammatory factors (e.g., nitric oxide) that may influence IL-6 levels by modulating protein clearance.